Glutamate signaling and transport around nodes of Ranvier and internodal myelin regions.

The roles of glutamate as a major building block of proteins and as a key participant in numerous metabolic pathways are well established. Likewise, glutamate's function as a neurotransmitter-along with the distribution and actions of its receptors and reuptake mechanisms within the brain's gray matter-has been extensively characterized, leading to the development of existing and emerging treatments for neurological and psychiatric disorders. More recently, it has become clear that glutamate is also released in significant amounts within the white matter (WM), where it acts on specific receptors and is taken up by dedicated transporters. In the WM, glutamate is essential for activating receptors that support the development and maintenance of myelinated axons. Growing evidence further indicates that elevated extracellular glutamate or impaired glial reuptake in the WM can lead to pathological outcomes. Many of the receptors and transporters involved in glutamate signaling are located on astrocytic membranes and on the oligodendrocyte-derived myelin sheath, particularly concentrated at nodes of Ranvier and the adjacent paranodal and juxtaparanodal regions. This expanding understanding of glutamate-related mechanisms in the WM may ultimately pave the way for new therapeutic strategies targeting WM pathologies.